US5877289A
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Tissue factor compositions and ligands for the specific coagulation of vasculature
Assignee: Scripps Research Institute
•
Filing: 1995-06-07
•
Granted: 1999-03-02
•
Expires: 2015-06-07
Abstract
Abstract Disclosed are various compositions and methods for use in achieving specific blood coagulation. This is exemplified by the specific in vivo coagulation of tumor vasculature, causing tumor regression, through the site-specific delivery of a coagulant using a bispecific antibody.
Inventors
- 👤 Philip E. Thorpe
- 👤 Thomas S. Edgington
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-23 14:43
CPC Classifications
C; C07; C07K; C07K16/00; C07K16/18; C07K16/28; C07K16/30; C07K16/3015; A; A61; A61K; A61K47/00; A61K47/50; A61K47/51; A61K47/68; A61K47/6835; A61K47/6849; A61K47/6851; A61P; A61P35/00; A61P7/00; A61P7/04; C07K14/00; C07K14/435; C07K14/705; C07K14/70596; C07K16/22; C07K16/2803; C07K16/2818; C07K16/2833; C07K16/2896; A61K39/00; A61K2039/505; A61K2123/00; A61K38/00; C07K2317/00; C07K2317/30; C07K2317/31; C07K2317/32; C07K2317/34; C07K2317/50; C07K2317/55
Claims Analysis
Total Claims: 108
Claim 1
Independent Claim
66 words
A binding ligand comprising: (a) a first binding region that binds to a tumor cell, a component of tumor-associated vasculature or a component of tumor-associated stroma; the first binding region operatively linked to (b) a Tissue Factor construct or a second binding region that binds to a Tissue Factor construct, wherein said second binding region comprises an antibody or an antigen binding region of an antibody.
Claim 2
Dependent Claim
66 words
A binding ligand comprising: (a) a first binding region that binds to a tumor cell, a component of tumor-associated vasculature or a component of tumor-associated stroma; the first binding region operatively linked to (b) a Tissue Factor construct or a second binding region that binds to a Tissue Factor construct, wherein said second binding region comprises an antibody or an antigen binding region of an antibody.
Claim 3
Dependent Claim
24 words
The binding ligand of claim 1, wherein said Tissue Factor construct comprises a mutant Tissue Factor deficient in the ability to activate Factor VII.
Claim 4
Dependent Claim
27 words
The binding ligand of claim 2, wherein said Tissue Factor construct includes a mutation in the amino acid region between about position 157 and about position 167.
Claim 5
Dependent Claim
57 words
The binding ligand of claim 3, wherein, within said Tissue Factor construct, Trp at position 158 is changed to Arg; wherein Ser at position 162 is changed to Ala; wherein Gly at position 164 is changed to Ala; or wherein Trp at position 158 is changed to Arg and Ser at position 162 is changed to Ala.
Claim 6
Dependent Claim
16 words
The binding ligand of claim 1, wherein said Tissue Factor construct comprises a truncated Tissue Factor.
Claim 7
Dependent Claim
24 words
The binding ligand of claim 5, wherein said truncated Tissue Factor comprises amino acids 1 to about 219 of the mature Tissue Factor protein.
Claim 8
Dependent Claim
20 words
The binding ligand of claim 5, wherein said truncated Tissue Factor has the amino acid sequence of SEQ ID NO:23.
Claim 9
Dependent Claim
33 words
The binding ligand of claim 1, wherein said Tissue Factor construct comprises a first Tissue Factor or truncated Tissue Factor construct operatively linked to a second Tissue Factor or truncated Tissue Factor construct.
Claim 10
Dependent Claim
16 words
The binding ligand of claim 8, wherein said Tissue Factor construct comprises two truncated Tissue Factors.
Claim 11
Dependent Claim
16 words
The binding ligand of claim 9, wherein said Tissue Factor construct comprises three truncated Tissue Factors.
Claim 12
Dependent Claim
16 words
The binding ligand of claim 10, wherein said Tissue Factor construct comprises five truncated Tissue Factors.
Claim 13
Dependent Claim
28 words
The binding ligand of claim 8, wherein said Tissue Factor construct comprises a first and second Tissue Factor construct operatively linked via a disulfide, thioether or peptide bond.
Claim 14
Dependent Claim
39 words
The binding ligand of claim 1, wherein said Tissue Factor construct comprises a Tissue Factor construct with a hydrophobic membrane insertion moiety, and wherein said Tissue Factor construct is linked to said first binding region via a biologically-releasable bond.
Claim 15
Dependent Claim
18 words
The binding ligand of claim 1, comprising a first binding region operatively linked to said Tissue Factor construct.
Claim 16
Dependent Claim
22 words
The binding ligand of claim 14, wherein said first binding region is linked to said Tissue Factor construct via a biologically-releasable bond.
Claim 17
Dependent Claim
29 words
The binding ligand of claim 15, wherein said first binding region is inked via a biologically-releasable bond to a Tissue Factor construct that comprises a hydrophobic membrane insertion moiety.
Claim 18
Dependent Claim
36 words
The binding ligand of claim 16, wherein said Tissue Factor construct comprises a truncated Tissue Factor that includes a hydrophobic membrane insertion moiety comprising a stretch of between about 3 and about 20 hydrophobic amino acids.
Claim 19
Dependent Claim
30 words
The binding ligand of claim 17, wherein said hydrophobic membrane insertion moiety comprises a stretch of hydrophobic amino acids located at the N- or C-terminus of the truncated Tissue Factor.
Claim 20
Dependent Claim
27 words
The binding ligand of claim 16, wherein said Tissue Factor construct comprises a truncated Tissue Factor that includes a hydrophobic membrane insertion moiety comprising a fatty acid.
Claim 21
Dependent Claim
25 words
The binding ligand of claim 16, wherein said Tissue Factor construct comprises two truncated Tissue Factors, each of which includes a hydrophobic membrane insertion moiety.
Claim 22
Dependent Claim
23 words
The binding ligand of claim 15, wherein said first binding region is linked to said Tissue Factor construct via a selectively-cleavable peptide bond.
Claim 23
Dependent Claim
38 words
The binding ligand of claim 21, wherein said first binding region is linked to said Tissue Factor construct via a peptide linker that includes a cleavage site for urokinase, plasmin, Thrombin, Factor IXa, Factor Xa or a metalloproteinase.
Claim 24
Dependent Claim
36 words
The binding ligand of claim 22, wherein said first binding region is linked to said Tissue Factor construct via a peptide linker that includes a cleavage site for an interstitial collagenase, a gelatinase or a stromelysin.
Claim 25
Dependent Claim
40 words
The binding ligand of claim 1, comprising a first binding region operatively linked to a second binding region that binds to said Tissue Factor construct, said second binding region comprising an antibody or an antigen binding region of an antibody.
Claim 26
Dependent Claim
22 words
The binding ligand of claim 24, wherein said first binding region is an antibody or an antigen binding region of an antibody.
Claim 27
Dependent Claim
19 words
The binding ligand of claim 24, wherein said second binding region comprises an IgG antibody or an IgM antibody.
Claim 28
Dependent Claim
24 words
The binding ligand of claim 24, wherein said second binding region comprises an scFv, Fv, Fab', Fab or F(ab') 2 fragment of an antibody.
Claim 29
Dependent Claim
24 words
The binding ligand of claim 24, further comprising a Tissue Factor construct bound to said second antibody or antigen binding region of an antibody.
Claim 30
Dependent Claim
22 words
The binding ligand of claim 1, wherein said first binding region comprises an antibody or an antigen binding region of an antibody.
Claim 31
Dependent Claim
19 words
The binding ligand of claim 25, wherein said first binding region comprises an IgG antibody or an IgM antibody.
Claim 32
Dependent Claim
24 words
The binding ligand of claim 29, wherein said first binding region comprises an scFv, Fv, Fab', Fab or F(ab') 2 fragment of an antibody.
Claim 33
Dependent Claim
66 words
The binding ligand of claim 29, wherein said first binding region comprises an antigen binding region of an antibody that binds to the tumor cell surface antigen p185 HER2 , milk mucin core protein, TAG-72, Lewis a, carcinoembryonic antigen (CEA) or a tumor-associated antigen that binds to an antibody selected from the group consisting of B3 (ATCCHB10573), KS1/4 (NRRLB/18536 and NRRLB/18537), 260F9 (ATCCHB8488) and D612 (ATCCHB9796).
Claim 34
Dependent Claim
36 words
The binding ligand of claim 29, wherein said first binding region comprises an antigen binding region of an antibody that binds to a surface-expressed, surface-accessible or surface-localized component of intratumoral blood vessels of a vascularized tumor.
Claim 35
Dependent Claim
28 words
The binding ligand of claim 33, wherein said first binding region comprises an antigen binding region of an antibody that binds to a tumor vasculature cell surface receptor.
Claim 36
Dependent Claim
51 words
The binding ligand of claim 34, wherein said first binding region comprises an antigen binding region of an antibody that binds to an MHC Class II protein, a VEGF/VPF receptor, an FGF receptor, a TGFβ receptor, a TIE, VCAM-1, ICAM-1, P-selectin, E-selectin, α v β 3 integrin, pleiotropin, endosialin or endoglin.
Claim 37
Dependent Claim
27 words
The binding ligand of claim 35, wherein said first binding region comprises an antigen binding region of an antibody that binds to an MHC Class II protein.
Claim 38
Dependent Claim
25 words
The binding ligand of claim 35, wherein said first binding region comprises an antigen binding region of an antibody that binds to a VEGF/VPF receptor.
Claim 39
Dependent Claim
23 words
The binding ligand of claim 35, wherein said first binding region comprises an antigen binding region of an antibody that binds to VCAM-1.
Claim 40
Dependent Claim
23 words
The binding ligand of claim 35, wherein said first binding region comprises an antigen binding region of an antibody that binds to ICAM-1.
Claim 41
Dependent Claim
23 words
The binding ligand of claim 35, wherein said first binding region comprises an antigen binding region of an antibody that binds to P-selectin.
Claim 42
Dependent Claim
23 words
The binding ligand of claim 35, wherein said first binding region comprises an antigen binding region of an antibody that binds to E-selectin.
Claim 43
Dependent Claim
23 words
The binding ligand of claim 35, wherein said first binding region comprises an antigen binding region of an antibody that binds to endoglin.
Claim 44
Dependent Claim
33 words
The binding ligand of claim 42, wherein said first binding region comprises an antigen binding region of an antibody that binds to the same epitope as the monoclonal antibody TEC-4 (ATCC HB 12312).
Claim 45
Dependent Claim
24 words
The binding ligand of claim 43, wherein said first binding region comprises an antigen binding region of the monoclonal antibody TEC-4 (ATCC HB 12312).
Claim 46
Dependent Claim
32 words
The binding ligand of claim 42, wherein said first binding region comprises an antigen binding region of an antibody that binds to the same epitope as the monoclonal antibody TEC-11 (ATCC HB-12311).
Claim 47
Dependent Claim
23 words
The binding ligand of claim 45, wherein said first binding region comprises an antigen binding region of the monoclonal antibody TEC-11 (ATCC HB-12311).
Claim 48
Dependent Claim
36 words
The binding ligand of claim 33, wherein said first binding region comprises an antigen binding region of an antibody that binds to a ligand or growth factor that binds to a tumor vasculature cell surface receptor.
Claim 49
Dependent Claim
49 words
The binding ligand of claim 47, wherein said first binding region comprises an antigen binding region of an antibody that binds to VEGF/VPF, FGF, TGFβ, a ligand that binds to a TIE, a tumor-associated fibronectin isoform, scatter factor, hepatocyte growth factor (HGF), platelet factor 4 (PF4), PDGF or TIMP.
Claim 50
Dependent Claim
23 words
The binding ligand of claim 48, wherein said first binding region comprises an antigen binding region of an antibody that binds to VEGF/VPF.
Claim 51
Dependent Claim
33 words
The binding ligand of claim 49, wherein said first binding region comprises an antigen binding region of an antibody that binds to the same epitope as the monoclonal antibody GV39 (ATCC HB 12450).
Claim 52
Dependent Claim
24 words
The binding ligand of claim 50, wherein said first binding region comprises an antigen binding region of the monoclonal antibody GV39 (ATCC HB 12450).
Claim 53
Dependent Claim
33 words
The binding ligand of claim 49, wherein said first binding region comprises an antigen binding region of an antibody that binds to the same epitope as the monoclonal antibody GV97 (ATCC HB 12451).
Claim 54
Dependent Claim
24 words
The binding ligand of claim 52, wherein said first binding region comprises an antigen binding region of the monoclonal antibody GV97 (ATCC HB 12451).
Claim 55
Dependent Claim
23 words
The binding ligand of claim 48, wherein said first binding region comprises an antigen binding region of an antibody that binds to FGF.
Claim 56
Dependent Claim
23 words
The binding ligand of claim 48, wherein said first binding region comprises an antigen binding region of an antibody that binds to TGFβ.
Claim 57
Dependent Claim
59 words
The binding ligand of claim 33, wherein said first binding region comprises an antigen binding region of an antibody that binds to a ligand:receptor complex or a growth factor:receptor complex, but does not bind to the ligand or growth factor or to the receptor when the ligand or growth factor or the receptor is not in the ligand:receptor complex.
Claim 58
Dependent Claim
42 words
The binding ligand of claim 29, wherein said first binding region comprises an antigen binding region of an antibody that binds to a basement membrane component, tenascin, an activated platelet or an antigen inducible on a basement membrane component or activated platelet.
Claim 59
Dependent Claim
30 words
The binding ligand of claim 33, wherein said first binding region is operatively linked to a second antibody or antigen binding region thereof that binds to a Tissue Factor construct.
Claim 60
Dependent Claim
33 words
The binding ligand of claim 1, wherein said first binding region comprises a ligand or receptor that binds to a tumor cell, a component of tumor vasculature or a component of tumor stroma.
Claim 61
Dependent Claim
47 words
The binding ligand of claim 59, wherein said first binding region comprises VEGF/VPF, FGF, TGFβ, a ligand that binds to a TIE, a tumor-associated fibronectin isoform, scatter factor, hepatocyte growth factor (HGF), platelet factor 4 (PF4), PDGF, TIMP or a soluble binding domain of a VEGF/VPF receptor.
Claim 62
Dependent Claim
13 words
The binding ligand of claim 60, wherein said first binding region comprises VEGF/VPF.
Claim 63
Dependent Claim
58 words
The binding ligand of claim 1, comprising a first antibody or antigen binding region of an antibody that binds to a tumor cell, a component of tumor-associated vasculature or a component of tumor-associated stroma; the first binding region operatively linked to a second antibody or antigen binding region of an antibody that binds to a Tissue Factor construct.
Claim 64
Dependent Claim
28 words
The binding ligand of claim 1, wherein said first binding region is operatively linked to said Tissue Factor construct or said second binding region via a covalent bond.
Claim 65
Dependent Claim
27 words
The binding ligand of claim 10, wherein said first binding region is operatively linked to said Tissue Factor construct or said second binding region via a cross-linker.
Claim 66
Dependent Claim
57 words
The binding ligand of claim 10, wherein said binding ligand is a fusion protein prepared by expressing a recombinant vector in a host cell, wherein the vector comprises, in the same reading frame, a DNA segment encoding said first binding region operatively linked to a DNA segment encoding said Tissue Factor construct or said second binding region.
Claim 67
Dependent Claim
12 words
The binding ligand of claim 1, dispersed in a pharmacologically acceptable medium.
Claim 68
Dependent Claim
42 words
A binding ligand comprising a first antibody or antigen binding region of an antibody that binds to a tumor cell, a component of tumor-associated vasculature or a component of tumor-associated stroma; the first binding region operatively linked to a Tissue Factor construct.
Claim 69
Dependent Claim
42 words
A binding ligand comprising a first antibody or antigen binding region of an antibody that binds to a tumor cell, a component of tumor-associated vasculature or a component of tumor-associated stroma; the first binding region operatively linked to a Tissue Factor construct.
Claim 70
Dependent Claim
55 words
A binding ligand comprising a first antibody or antigen binding region of an antibody that binds to a tumor cell, a component of tumor-associated vasculature or a component of tumor-associated stroma; the first binding region operatively linked to a second antibody or antigen binding region of an antibody that binds to a Tissue Factor construct.
Claim 71
Dependent Claim
55 words
A binding ligand comprising a first antibody or antigen binding region of an antibody that binds to a tumor cell, a component of tumor-associated vasculature or a component of tumor-associated stroma; the first binding region operatively linked to a second antibody or antigen binding region of an antibody that binds to a Tissue Factor construct.
Claim 72
Dependent Claim
60 words
A bispecific antibody comprising: (a) a first antibody or antigen binding region of an antibody that binds to a tumor cell, a component of tumor-associated vasculature or a component of tumor-associated stroma; the first antibody or antigen binding region operatively linked to (b) a second antibody or antigen binding region of an antibody that binds to a Tissue Factor construct.
Claim 73
Dependent Claim
60 words
A bispecific antibody comprising: (a) a first antibody or antigen binding region of an antibody that binds to a tumor cell, a component of tumor-associated vasculature or a component of tumor-associated stroma; the first antibody or antigen binding region operatively linked to (b) a second antibody or antigen binding region of an antibody that binds to a Tissue Factor construct.
Claim 74
Dependent Claim
52 words
A binding ligand comprising a first binding region that binds to a surface-expressed, surface-accessible or surface-localized marker of intratumoral blood vessels of a vascularized tumor, the first binding region operatively linked to a Tissue Factor construct or to an antibody, or antigen binding region thereof, that binds to a Tissue Factor construct.
Claim 75
Dependent Claim
52 words
A binding ligand comprising a first binding region that binds to a surface-expressed, surface-accessible or surface-localized marker of intratumoral blood vessels of a vascularized tumor, the first binding region operatively linked to a Tissue Factor construct or to an antibody, or antigen binding region thereof, that binds to a Tissue Factor construct.
Claim 76
Dependent Claim
60 words
A binding ligand comprising a first antibody, or antigen binding region thereof, that binds to a surface-expressed surface-accessible or surface-localized marker of intratumoral blood vessels of a vascularized tumor, the first antibody or antigen binding region operatively linked to a Tissue Factor construct or to a second antibody, or antigen binding region thereof, that binds to a Tissue Factor construct.
Claim 77
Dependent Claim
60 words
A binding ligand comprising a first antibody, or antigen binding region thereof, that binds to a surface-expressed surface-accessible or surface-localized marker of intratumoral blood vessels of a vascularized tumor, the first antibody or antigen binding region operatively linked to a Tissue Factor construct or to a second antibody, or antigen binding region thereof, that binds to a Tissue Factor construct.
Claim 78
Dependent Claim
22 words
The binding ligand of claim 71; wherein said first antibody, or antigen binding region thereof, is linked to a Tissue Factor construct.
Claim 79
Dependent Claim
33 words
The binding ligand of claim 71, wherein said first antibody, or antigen binding region thereof, is linked to a second antibody, or antigen binding region thereof, that binds to a Tissue Factor construct.
Claim 80
Dependent Claim
20 words
A Tissue Factor construct comprising an operatively linked first, second and third Tissue Factor construct or truncated Tissue Factor construct.
Claim 81
Dependent Claim
20 words
A Tissue Factor construct comprising an operatively linked first, second and third Tissue Factor construct or truncated Tissue Factor construct.
Claim 82
Dependent Claim
19 words
The Tissue Factor construct of claim 74, comprising about five operatively linked Tissue Factor or truncated Tissue Factor constructs.
Claim 83
Dependent Claim
19 words
The Tissue Factor construct of claim 75, comprising about ten operatively linked Tissue Factor or truncated Tissue Factor constructs.
Claim 84
Dependent Claim
19 words
The Tissue Factor construct of claim 76, comprising about twenty operatively linked Tissue Factor or truncated Tissue Factor constructs.
Claim 85
Dependent Claim
14 words
The Tissue Factor construct of claim 74, comprising at least one truncated Tissue Factor.
Claim 86
Dependent Claim
25 words
The Tissue Factor construct of claim 78, wherein said truncated Tissue Factor comprises amino acids 1 to about 219 of the mature Tissue Factor protein.
Claim 87
Dependent Claim
21 words
The Tissue Factor construct of claim 78, wherein said truncated Tissue Factor has the amino acid sequence of SEQ ID NO:23.
Claim 88
Dependent Claim
19 words
The Tissue Factor construct of claim 78, comprising a truncated Tissue Factor that includes a hydrophobic membrane insertion moiety.
Claim 89
Dependent Claim
26 words
The Tissue Factor construct of claim 81, comprising a truncated Tissue Factor that includes a stretch of between about 3 and about 20 hydrophobic amino acids.
Claim 90
Dependent Claim
31 words
The Tissue Factor construct of claim 82, comprising a truncated Tissue Factor that includes a stretch of hydrophobic amino acids located at the N- or C-terminus of the truncated Tissue Factor.
Claim 91
Dependent Claim
17 words
The Tissue Factor construct of claim 81, comprising a truncated Tissue Factor that includes a fatty acid.
Claim 92
Dependent Claim
21 words
The Tissue Factor construct of claim 81, comprising two truncated Tissue Factors, each of which includes a hydrophobic membrane insertion moiety.
Claim 93
Dependent Claim
19 words
The Tissue Factor construct of claim 78, comprising a truncated Tissue Factor modified to contain a terminal cysteine residue.
Claim 94
Dependent Claim
23 words
The Tissue Factor construct of claim 86, comprising two truncated Tissue Factors, each of which is modified to contain a terminal cysteine residue.
Claim 95
Dependent Claim
25 words
The Tissue Factor construct of claim 86, further comprising an antibody or an antigen binding region of an antibody operatively linked to said cysteine residue.
Claim 96
Dependent Claim
20 words
The Tissue Factor construct of claim 78, comprising a truncated Tissue Factor modified to contain a selectively cleavable peptide linker.
Claim 97
Dependent Claim
28 words
The Tissue Factor construct of claim 89, wherein said selectively cleavable peptide linker includes a cleavage site for urokinase, plasmin, Thrombin, Factor IXa, Factor Xa or a metalloproteinase.
Claim 98
Dependent Claim
26 words
The Tissue Factor construct of claim 90, wherein said selectively cleavable peptide linker includes a cleavage site for an interstitial collagenase, a gelatinase or a stromelysin.
Claim 99
Dependent Claim
27 words
The Tissue Factor construct of claim 89, further comprising an antibody or an antigen binding region of an antibody operatively linked to said selectively cleavable peptide linker.
Claim 100
Dependent Claim
47 words
The Tissue Factor construct of claim 67, comprising an operatively linked series of units in the sequence: a cysteine residue, a selectively cleavable peptide linker, a stretch of hydrophobic amino acids, a first truncated Tissue Factor, a second truncated Tissue Factor, and a third truncated Tissue Factor.
Claim 101
Dependent Claim
25 words
The Tissue Factor construct of claim 93, further comprising an antibody or an antigen binding region of an antibody operatively linked to said cysteine residue.
Claim 102
Dependent Claim
55 words
The Tissue Factor construct of claim 93, comprising an operatively linked series of units in the sequence: a cysteine residue, a selectively cleavable peptide linker, a first stretch of hydrophobic amino acids, a first truncated Tissue Factor, a second truncated Tissue Factor, a third truncated Tissue Factor and a second stretch of hydrophobic amino acids.
Claim 103
Dependent Claim
68 words
The Tissue Factor construct of claim 95, comprising an operatively linked series of units in the sequence: a first cysteine residue, a selectively cleavable peptide linker, a first stretch of hydrophobic amino acids, a first truncated Tissue Factor, a second truncated Tissue Factor, a third truncated Tissue Factor, a second stretch of hydrophobic amino acids and a second cysteine residue or a second a selectively cleavable peptide linker.
Claim 104
Dependent Claim
27 words
The Tissue Factor construct of claim 96, comprising an antibody or an antigen binding region of an antibody operatively linked to said first or second cysteine residue.
Claim 105
Dependent Claim
52 words
A Tissue Factor construct comprising a first Tissue Factor or truncated Tissue Factor construct operatively linked to a second Tissue Factor or truncated Tissue Factor construct wherein at least one of said Tissue Factor or truncated Tissue Factor constructs is a mutant Tissue Factor deficient in the ability to activate Factor VII.
Claim 106
Dependent Claim
52 words
A Tissue Factor construct comprising a first Tissue Factor or truncated Tissue Factor construct operatively linked to a second Tissue Factor or truncated Tissue Factor construct wherein at least one of said Tissue Factor or truncated Tissue Factor constructs is a mutant Tissue Factor deficient in the ability to activate Factor VII.
Claim 107
Dependent Claim
28 words
The Tissue Factor construct of claim 98, comprising a Tissue Factor that includes a mutation in the amino acid region between about position 157 and about position 167.
Claim 108
Dependent Claim
58 words
The Tissue Factor construct of claim 99, comprising a mutant Tissue Factor wherein Trp at position 158 is changed to Arg; wherein Ser at position 162 is changed to Ala; wherein Gly at position 164 is changed to Ala; or wherein Trp at position 158 is changed to Arg and Ser at position 162 is changed to Ala.
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| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
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| 3.5 Years (Year 4) | 2002-03-01 | 2002-08-31 | 2003-03-02 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 2006-03-01 | 2006-08-31 | 2007-03-02 | $3760.00 | Window Closed / Lapsed |
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